An enduring alteration in the behavioral response to an acute psychostimulant challenge is produced by repeated psychostimulant pretreatment. Termed behavior sensitization, this example of neuronal plasticity can culminate in paranoid psychosis, panic attacks and anxiety disorders. Using a rat animal model, sensitization can be studied in two temporally and spatially distinct components, initiation and expression. The study of initiation attempts to describe the neural and cellular substrates upon which repeated drug administration impinges to establish the long-term behavioral alterations. The study of expression endeavors to identify enduring changes in neural and cellular function that mediate the augmented behavioral response. During the previous funding period it was shown that the initiation of sensitization to cocaine arises from drug action in the ventral tegmental area (VTA) and that the expression of sensitization is partly the result of altered excitatory amino acid (EAA) and dopamine transmission in the nucleus accumbens. In this proposal, rats will be treated with repeated cocaine injections for one week, and models of the synaptic organization in the VTA and nucleus accumbens in the initiation and expression of sensitization to repeated cocaine will be tested. These models provide a basis for evaluating not only dopamine transmission, but other neurotransmitters arising from intrinsic and afferent projections to the VTA and nucleus accumbens, including EAAs, gamma-aminobutyric acid (GABA) and the opioid peptide, enkephalin. Rats will be examined at early and late withdrawal times to characterize the time course of biochemical changes that may parallel the time course of behavioral sensitization. A combination of behavioral pharmacology, microdialysis and biochemical measures of signal transduction will be used to identify alterations in neurotransmission. By identifying the neural substrates of sensitization to cocaine it will be possible to provide rational interventions in treating the sensitization-based psychopathologies present in some cocaine addicts.